1. Field of the Invention
The present invention relates to a medical composition for inhibiting tumor cell growth. In particular, it relates to a complex immuno-gene medical composition for inhibiting tumor cell growth and a method for inhibiting tumor cell growth using such medical composition.
2. The Prior Arts
Canine transmissible venereal tumor (CTVT) is a naturally occurring, poorly differentiated tumor cell. The growth of the CTVT is similar to an allograft. CTVT are transmitted in Canines by mating, biting or contacting, wherein viable tumor cells enter through injured skin or mucus.
In an experimental model, CTVT shows an expected growth pattern. The growth phases in the CTVT model include a Progressive phase (P phase), a Stasis phase (S phase), and a Regressive phase (R phase). CTVT expresses few major histocompatibility (MHC) molecules in the P phase but a large amount of transforming growth factor-β (TGF-β) in the P phase and the R phase. TGF-β is capable of inhibiting expression of MHC I and MHC II, and inhibiting activity of natural killer (NK) cells. Besides, 85% of tumor infiltrating lymphocytes (TILs) in CTVT are lymphocytes that are non-T or non-B cells, which are not able to express antigens characterized as T-cells and B-cells. From morphological observation, the aforementioned cells contain large granules in their cytoplasm similar to those found in NK cells. It is presumed that the non-T or non-B cells are NK cells.
Major histocompatibility complex (MHC) class I antigens are 44 kDa glycoproteins expressed on the cell plasma membrane associated with β2-microglobulin (β2m), and they are also known as histocompatibility leukocyte antigens (HLA) in humans.
Tumor cells grow by escaping the monitoring of the host immune system through many different mechanisms. One of the mechanisms used by tumor cells is a lack of or a low expression of MHC class I antigens. For example, Human tumor cells including primary breast carcinoma, advanced renal cell carcinoma, melanoma, prostate cancer, lung carcinoma, and other tumor sources from colon, bladder, skin and endometrium have been found to express low MHC levels, and some cancer cells even express no MHC. In animals, low expression of MHC is also found in T lymphoma caused by Marek's disease virus in poultry and CTVT occurring in canines.
According to the “missing self” hypothesis, when tumor cells express low or no MHC, the activating receptors on the surface of the natural killer (NK) cells in the host are activated, and the NK cells recognize and kill the target cells. However, many tumor cells secrete transforming growth factors to inhibit the cytotoxicity of NK cells. Therefore, the inability of host immune system to function normally is one of the reasons for the tumor cells to grow rapidly without much constraint.
TGF-β is a 25 kDa homodimerric protein with very potent pleiotropic regulatory effects on the mammalian immune system. Addition of exogenous TGF-β to a culture of lymphocytes decreases the proliferation of B cells, mature T cells, thymocytes, NK cells and lymphokine-activated killer (LAK) cells. Currently, It is known that many tumor cells including colorectal cancer, mammary tumor, thyreoglandular cancer, hepatocellular carcinoma (HCC) and Meth A tumor produce TGF-β. TGF-β is capable of aiding in the growth of tumors by enhancing angiogenesis and cell adhesion. Moreover, the tumor cells evade the host immune surveillance by low MHC and low intercellular adhesion molecule-1(ICAM-1) expressions.
An antagonism or reduced secretion of TGF-β is a possible way to restore the normal function of a host immune system and fight against tumor cells. Methods of immuno-therapy for inhibiting TGF-β are presented herein. Administration of TGF-β antibody by injection and gene therapy with antisense oligonucleotide are the other two major methods.
T lymphocytes cannot function to kill tumor cells that secrete TGF-β or express no or low MHC. Accordingly, NK cells play important roles against tumor cells expressing no or low MHC. NK cells differentiation-related cytokines have proved to be successful in removing tumor cells. Those cytokines including γ-interferon (INF-γ), interleukin-2 (IL-2), IL-12, IL-15, IL-18 and IL-21. They are related to the functions of T lymphocytes, B lymphocytes, NK cells and other immune cells.
It is demonstrated that several cytokines are effective against tumor cells in some in vitro and animal experiments. Those researches focus upon the application of cytokines to cancer therapy. There are two kinds of cytokines that have been used against cancer cells. One kind is T-helper type 1 (Th1) cytokine, which stimulates reactions related to IL-2 and INF-γ production, and to the following cellular immunity, including IL-2, IL-12, IL-15, IL-18 and INF-γ. Another kind is T-helper type 2 (Th2) cytokine, which stimulates reactions related to production of IL-4, IL-5 and IL-6 (these three cytokines stimulate B lymphocytes to grow and differentiate), and which induces humoral immunity. However, results from those clinical researches using immuno-therapy of cytokines reveal that factors such as the method of administration, the amount administered, kinds of tumors, other additional cytokines or drugs, or potential side effects, and so on, are important in therapeutic effectivity and clinical application. Although immuno-gene-therapy is effective against tumor cells, there are limitations in its practical application for conventional methods. Usage of a combination of various cytokines according to the immune characteristics of tumor cells may be a more applicable method in the fight against tumors.